Background <p>Renal progression remains a major unmet clinical challenge in patients with type 2 diabetes mellitus (T2DM). The hemoglobin glycation index (HGI), reflecting inter-individual variability in hemoglobin glycation independent of glucose levels, has been proposed as a complementary glycemic marker; however, its prognostic value for renal outcomes remains uncertain.</p> Methods <p>We conducted a prospective cohort study of 441 adults with T2DM followed at a tertiary medical center between 2016 and 2021. HGI was calculated as the difference between observed HbA1c and predicted HbA1c derived from fasting plasma glucose. Baseline and mean first-year HGI and HbA1c were categorized into tertiles. Renal progression was defined as new-onset albuminuria or a ≥ 30% decline in estimated glomerular filtration rate. Associations with renal progression were assessed using Cox proportional hazards models with sequential adjustment for demographic, metabolic, and treatment-related covariates.</p> Results <p>During a median follow-up of 61 months, 162 participants (36.7%) experienced renal progression. Higher baseline and mean first-year HGI were significantly associated with increased risk of renal progression across most multivariable models. In the fully adjusted model, participants in the highest tertile of mean first-year HGI had a 58% higher risk of renal progression compared with those in the lowest tertile (hazard ratio 1.58, 95% confidence interval 1.01–2.49). Baseline HbA1c was also associated with renal progression. In contrast, associations between HGI and new-onset retinopathy or all-cause mortality were not statistically significant after full adjustment.</p> Conclusions <p>Both HGI and HbA1c were independently associated with renal progression in patients with T2DM. These findings suggest that inter-individual variability in hemoglobin glycation may be associated with renal progression in patients with T2DM.</p>